U.S. patent number 11,298,449 [Application Number 14/300,179] was granted by the patent office on 2022-04-12 for systems and methods for performing medical procedures involving accessing the lymphatic system.
This patent grant is currently assigned to LXS, LLC. The grantee listed for this patent is Matthew J. Callaghan, Christian S. Eversull, Stephen A. Leeflang. Invention is credited to Matthew J. Callaghan, Christian S. Eversull, Stephen A. Leeflang.
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United States Patent |
11,298,449 |
Callaghan , et al. |
April 12, 2022 |
Systems and methods for performing medical procedures involving
accessing the lymphatic system
Abstract
System and methods are provided for treating a patient that
include a delivery device sized for introduction into a target site
within a patient's body, a source of one or more therapeutic and/or
diagnostic agents coupled to the delivery device, and a tubular
member sized for introduction into the patient's vasculature to
isolate the thoracic duct. Once the thoracic duct is isolated,
fluid may be removed from the thoracic duct, e.g., to prevent the
agents that transit from the target site into the thoracic duct
from entering the patient's vasculature, and/or to modulate flow
through the thoracic duct to modulate concentration and/or resident
time of the agents at the target site. The one or more agents may
include particles sized for preferential transit into the lymphatic
system.
Inventors: |
Callaghan; Matthew J.
(Stanford, CA), Eversull; Christian S. (Palo Alto, CA),
Leeflang; Stephen A. (Sunnyvale, CA) |
Applicant: |
Name |
City |
State |
Country |
Type |
Callaghan; Matthew J.
Eversull; Christian S.
Leeflang; Stephen A. |
Stanford
Palo Alto
Sunnyvale |
CA
CA
CA |
US
US
US |
|
|
Assignee: |
LXS, LLC (Palo Alto,
CA)
|
Family
ID: |
52006038 |
Appl.
No.: |
14/300,179 |
Filed: |
June 9, 2014 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20140364765 A1 |
Dec 11, 2014 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
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14160547 |
Jan 21, 2014 |
10111997 |
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14214882 |
Mar 15, 2014 |
10052059 |
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61832820 |
Jun 8, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61M
1/3615 (20140204); A61M 1/3496 (20130101); A61M
1/3609 (20140204); A61M 1/367 (20130101); A61M
1/3659 (20140204); A61M 1/3653 (20130101); A61B
10/0045 (20130101); A61M 2230/207 (20130101); A61M
2230/208 (20130101); A61M 2202/0405 (20130101); A61M
2205/3317 (20130101); A61M 2205/3306 (20130101) |
Current International
Class: |
A61M
1/36 (20060101); A61M 1/34 (20060101); A61B
10/00 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Other References
Pflug, J. and J. Calnan, The Valves of the Thoracic Duct at the
Angulus Venosus, Brit J. Surg, 1968, vol. 55, No. 12, December, 6
pages. cited by applicant .
Korean Intellectual Property Office, International Search Report
and Written Opinion for corresponding International Application No.
PCT/US2014/041445, Applicant: Matthew John Callaghan, dated Jun. 8,
2014, 16 pages. cited by applicant .
European Patent Office, Search Report for corresponding European
Application EP 15 808 427.0, Applicant: LXS, LLC, EPO Forms 1507S,
1703, and P04A42 ; dated Feb. 2, 2017, 10 pages. cited by
applicant.
|
Primary Examiner: Farrar; Lauren P
Assistant Examiner: Darb; Hamza A
Attorney, Agent or Firm: English; William A. Vista IP Law
Group LLP
Parent Case Text
This application claims benefit of co-pending provisional
application Ser. No. 61/832,820, filed Jun. 8, 2013, and is a
continuation-in-part of co-pending application Ser. No. 14/160,547,
filed Jan. 21, 2014, and Ser. No. 14/214,882, filed Mar. 15, 2014,
the entire disclosures of which are expressly incorporated by
reference herein.
Claims
We claim:
1. A method for treating a patient having a body including
vasculature and a lymphatic system including a thoracic duct,
comprising: injecting one or more therapeutic agents directly into
a target treatment site outside the lymphatic system within the
patient's body, the one or more therapeutic agents comprising
particles sized for preferential transit into the lymphatic system;
introducing a distal end of a tubular member into the vasculature
via a percutaneous access site; advancing the tubular member until
the distal end of the tubular member is disposed within a junction
of a left internal jugular vein and left subclavian vein and
adjacent the thoracic duct; sealing the thoracic duct using the
distal end of the tubular member to isolate the thoracic duct from
the junction; and removing fluid from the thoracic duct through the
tubular member to a location exterior to the patient's body,
thereby removing particles from the one or more therapeutic agents
that have transited into the thoracic duct.
2. The method of claim 1, wherein the particles have an outer
cross-section larger than thirty nanometers (30 nm).
3. The method of claim 2, wherein the particles have an outer
cross-section smaller than one hundred nanometers (100 nm).
4. The method of claim 1, wherein the one or more therapeutic
agents comprise a chemotherapy agent encapsulated within a lipid
membrane.
5. The method of claim 1, further comprising: removing the
particles from the removed fluid via one or more external
components exterior to the patient's body; and returning at least a
portion of the removed fluid from the one or more external
components into the thoracic duct through the tubular member after
removing the particles.
6. The method of claim 1, wherein sealing the thoracic duct
comprises: manipulating the tubular member to direct the distal end
into the thoracic duct; and expanding an expandable member on the
distal end to isolate the thoracic duct from the patient's
vasculature.
7. The method of claim 1, further comprising analyzing the removed
fluid to detect whether the one or more therapeutic agents are
present in the removed fluid, thereby identifying when the one or
more therapeutic agents have transited into the thoracic duct.
8. The method of claim 7, wherein the removed fluid is analyzed to
determine a concentration of the one or more therapeutic agents in
the removed fluid.
9. The method of claim 8, further comprising returning the removed
fluid into the patient's body before the one or more therapeutic
agents have been detected in the removed fluid.
10. The method of claim 1, further comprising controlling a flow
rate of fluid removed from the thoracic duct to control a resident
time of the one or more therapeutic agents at the target treatment
site.
11. The method of claim 1, wherein the target treatment site
comprises a tumor.
12. The method of claim 1, wherein injecting the one or more
therapeutic agents comprises injecting one or more chemotherapy
agents into the target treatment site to treat cancer at the target
treatment site.
13. A method for treating a patient having a body including a
lymphatic system including a thoracic duct, comprising: injecting a
therapeutic agent into interstitial tissue adjacent a target site
within a patient's body outside the thoracic duct, the therapeutic
agent sized for preferential transit into the lymphatic system; and
subsequently modulating flow from the thoracic duct to modulate one
or both of resident time and concentration of the therapeutic agent
within the tissue at the target site.
14. The method of claim 13, wherein the therapeutic agent moves
into, remains within, or transits within the lymphatic system from
the target site.
15. The method of claim 13, wherein modulating flow from the
patient's thoracic duct comprises collecting lymph from the
thoracic duct, the method further comprising: monitoring agent
concentration within the collected lymph; and discontinuing
collecting lymph when the agent concentration reaches a
predetermined threshold.
16. The method of claim 15, wherein collecting lymph comprises:
introducing a tubular member into vasculature within the patient's
body; using the tubular member to isolate the thoracic duct from
the vasculature; and collecting the lymph from the thoracic duct
using the tubular member.
17. A method for treating a patient having a body including a
lymphatic system including a thoracic duct, comprising: injecting
one or more therapeutic agents into interstitial tissue within the
patient's body outside the thoracic duct, the one or more
therapeutic agents sized for preferential transit into the
lymphatic system; and modulating lymph output from the thoracic
duct to manipulate delivery of the one or more therapeutic agents
within the patient's body.
18. The method of claim 17, wherein modulating lymph output
comprises at least one of modulating flow and volume of lymph from
the thoracic duct.
19. The method of claim 17, wherein modulating lymph output
comprises modifying or eliminating a natural return path of lymph
into a venous system of the patient's body.
20. The method of claim 17, wherein modulating lymph output
comprises: introducing a tubular member into vasculature within the
patient's body; using the tubular member to isolate the thoracic
duct from the vasculature; and selectively removing lymph from the
thoracic duct using the tubular member.
21. The method of claim 17, wherein the interstitial tissue is
located in or around a tumor.
22. The method of claim 21, wherein the tumor is located in one of
the patient's breast, ovary, lung, and gastrointestinal (GI) tract.
Description
FIELD OF THE INVENTION
The present invention relates generally to apparatus and methods
used to perform medical procedures, and, more particularly, to
systems and methods for performing medical procedures that include
accessing and/or otherwise involving the lymphatic system of a
patient, e.g., to facilitate localized delivery and/or removal of
compounds, e.g., therapeutic and/or diagnostic compounds introduced
into a patient's body.
BACKGROUND
Cancer is the second leading cause of death in the United States.
Current treatments focus on surgical excision of cancerous tissue,
radiation, systemic and localized chemotherapy and more recently
immunotherapy. Using systemic chemotherapy, it is difficult to
deliver high doses specifically to tumor cells without affecting
surrounding tissue and triggering severe systemic side effects.
Furthermore, although a high percentage of tumor cells metastasize
through the lymphatic system, raising drug levels in the lymphatic
system has proven especially challenging.
The lymphatic system includes a network of vessels generally
separate from veins and arteries. Rather than whole blood, the
lymphatic vessels carry lymphatic fluid (or lymph). The lymphatic
system serves a variety of physiologic purposes, including
returning interstitial fluid to the vascular space, transporting
fats from the digestive tract, and transporting immune-mediating
cells. The composition of lymphatic fluid is similar to plasma. It
contains white blood cells, but generally does not contain red
blood cells, platelets, or various other components of whole blood.
The lymphatic system culminates in a single large channel called
the thoracic duct, which joins the central venous system at the
confluence of the left internal jugular and subclavian veins.
Historically, the lymphatic system has been directly accessed
rarely in medical procedures. For example, some diagnostic
procedures involve direct cannulation of peripheral lymphatic
vessels, e.g., to infuse dye for identification of lymph nodes.
Direct access of the central lymphatic vessels, such as the
thoracic duct, is generally avoided. For example, a defect created
in the thoracic duct generally does not readily close on its own,
leading to significantly morbid conditions, such as chylothorax
(persistent collection of lymphatic fluid around the lungs).
The lymphatic system does, however, eventually drain into the
vasculature. A majority of lymphatic vessels come to a confluence
in the thoracic duct which generally enters the venous system at
the junction of the left subclavian vein and the left internal
jugular vein. A series of valves generally facilitate one-way flow
of lymphatic fluid into the venous system and prevent reflux of
whole blood into the thoracic duct. Although not well studied,
disruption of one or more of these valves may have negative
consequences. Therefore, it may be desirable to protect these
valves and/or the lymphatic vessels themselves from damage.
SUMMARY
The present invention is directed generally to systems and methods
for performing medical procedures. More particularly, the present
invention is direct to systems and methods for performing medical
procedures that include accessing the lymphatic system of a
patient, e.g., to remove, separate, and/or re-infuse lymphatic
fluid, e.g., to facilitate localized delivery of therapeutic and/or
diagnostic agents and/or removal of such agents within the
lymphatic system.
The lymphatic system is a network of channels draining local and
regional lymph nodes and carrying protein, lymphocytes, and plasma
from the interstitium back to the venous circulation. The lymphatic
system culminates in a single large channel called the thoracic
duct, which joins the central venous system at the confluence of
the left internal jugular and subclavian veins. At the level of the
capillary bed, lymphatic channels consist of overlapping
fenestrations, permitting uptake of macrolecules and compounds too
large to return through venous capillaries.
It has been shown that interstitially injected compounds or
particles smaller than about one hundred nanometers (100 nm) but
larger than about thirty to forty nanometers (30-40 nm) pass freely
from the interstitium into the lymphatic capillary channels.
Compounds larger than about one hundred nanometers (100 nm) remain
confined to the site of injection, while compounds smaller than
about forty nanometers (40 nm) may pass into venous capillaries.
Uptake and passage may be further affected by charge and shape of
the compounds.
Recently, new formulations of existing chemotherapy agents have
been designed to reduce systemic complications by prolonged
circulation time and preferential residence in interstitial
tissues. Liposomal formulations have proven the most efficient and
are available for intravenous injection in end-stage cancers of the
breast, ovary, and lung.
In a similar manner, carriers for chemotherapeutic agents may be
specifically designed for preferential uptake by local lymphatic
channels when injected either directly into or adjacent to
cancerous tissue. Recent animal studies using liposomal
preparations of doxorubicin demonstrate this principle. However,
while this technique may improve drug concentration in lymphatic
channels, it does not limit systemic toxicity. The injected drug
will eventually collect in the thoracic duct and be returned to the
venous circulation, e.g., within approximately twenty four (24)
hours. The systems and methods described herein may facilitate
local drug concentration in and around a tumor while limiting
systemic side effects by using the lymphatic system.
Another limitation of current methods is a dependence on peripheral
blood samples to monitor for circulating tumor cells. Recent
technology has advanced detection of these cells in peripheral
blood although cells in circulation are still quite rare. Tumor
cells are known to transit the lymphatic system, sometimes
preferentially, and therefore detection methods to analyze cells
within lymphatic fluid would be of significant benefit in cancer
detection and treatment.
The systems and methods herein may facilitate accessing and
capturing lymphatic output from the thoracic duct. Flow may be
monitored, regulated (including flow rate), diverted, discarded,
and/or selectively returned to circulation. Thus, in the setting of
cancer therapy, therapeutic agents may be introduced into the body
in such a way that at least part of the agents ultimately transits
the lymphatic system. In an exemplary embodiment, such agents may
be designed to preferentially move into and transit within the
lymphatic system. Such agents may be introduced locally into
tissue, intravenously, intra-arterially, or into other body
cavities. Alternatively, agents may be introduced directly into the
lymphatic system in either antegrade or retrograde directions.
Subsequently, output from the thoracic duct (or other lymphatic
channel) may be monitored, regulated, diverted, discarded, and/or
selectively returned to the body (e.g., intravenously or
otherwise). This may be done in such a way as to control dwell time
and/or transit, capture, removal, and/or recirculation of toxic
chemotherapeutic agents. In this manner, the effects of the agents
may be concentrated in local tissue (e.g., at a tumor site) or
within the lymphatic system (e.g., at the site of metastatic or
primary cancer cells) while minimizing exposure to the remainder of
the body, thus limiting toxicity.
In an exemplary embodiment, one or more agents may be introduced
locally in or around the site of a breast tumor. The agent(s) may
be sized or otherwise designed to cause preferential uptake by the
lymphatic system. The rate of local depletion may be modulated by
controlling the flow rate through the thoracic duct, for example,
by selective occlusion or flow restriction, e.g., using a catheter
or other device positioned within the thoracic duct. Further, in
addition or alternatively, the output of the thoracic duct may be
captured and discarded, such that lymph that contains the agent(s)
at relatively high levels is not re-circulated within the body,
which would otherwise cause systemic exposure. In this manner,
local concentrations and time of exposure of toxic chemotherapeutic
agents may be increased at the site of therapy without incurring
substantially deleterious systemic side effects.
In accordance with an exemplary embodiment, a system is provided
for treating a patient that includes a delivery device sized for
introduction into a target treatment site within a patient's body;
a source of one or more agents coupled to the delivery device, the
one or more agents comprising particles sized for preferential
transit into the lymphatic system; and a tubular member comprising
a proximal end, a distal end sized for introduction into the
patient's body into a thoracic duct, an expandable member on the
distal end for substantially sealing the thoracic duct from the
patient's venous system, and a lumen extending between the proximal
and distal ends for removing fluid from the thoracic duct including
the particles transiting into the thoracic duct.
In accordance with another embodiment, a method is provided for
treating a patient that includes delivering one or more agents into
a target treatment site within a patient's body, the one or more
agents comprising particles sized for preferential transit into the
lymphatic system; introducing a distal end of a tubular member into
the patient's vasculature via a percutaneous access site; advancing
the tubular member until the distal end is disposed within a
junction of the patient's left internal jugular vein and left
subclavian vein and adjacent the patient's thoracic duct; sealing
the thoracic duct using the distal end of the tubular member to
substantially isolate the thoracic duct from the junction; and
removing fluid from the thoracic duct through the tubular member to
a location exterior to the patient's body, thereby removing
particles from the one or more agents that have transited into the
thoracic duct.
In accordance with still another embodiment, a method is provided
for minimizing systemic exposure to one or more therapeutic or
diagnostic agents that includes locally introducing the one or more
agents into a patient's body, and subsequently collecting and/or
removing lymphatic fluid from the patient's thoracic duct. For
example, the one or more agents may be sized for preferential
uptake by the patient's lymphatic system, and the thoracic duct may
be isolated to prevent the one or more agents that transit into the
thoracic duct from entering the patient's venous system. Instead,
the one or more agents may be removed from the thoracic duct when
the lymphatic fluid is removed.
In accordance with yet another embodiment, a method is provided for
modulating one or both of residence time and concentration of one
or more therapeutic or diagnostic agents that includes delivering
the one or more agents locally into a target site within a
patient's body, and modulating flow of fluid through the patient's
thoracic duct.
Other aspects and features of the need for and use of the present
invention will become apparent from consideration of the following
description taken in conjunction with the accompanying
drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
It will be appreciated that the exemplary apparatus shown in the
drawings are not necessarily drawn to scale, with emphasis instead
being placed on illustrating the various aspects and features of
the illustrated embodiments. The drawings illustrate exemplary
embodiments of the invention, in which:
FIG. 1 is a perspective view of an exemplary embodiment of an
apparatus for accessing a thoracic duct.
FIGS. 2A and 2B are details of a distal portion of the apparatus of
FIG. 1, showing a balloon on the distal portion in collapsed and
enlarged configurations, respectively.
FIG. 2C is a cross-section of the distal portion of the apparatus
of FIGS. 2A-2B taken along line 2C-2C.
FIGS. 3A-3C are schematic views showing alternative relaxed shapes
for the distal portion of an apparatus, such as that shown in FIG.
1.
FIGS. 4A-4C are details of alternative embodiments of distal tips
that may be provided on an apparatus, such as that shown in FIGS.
1-2B.
FIG. 4D is a detail of another alternative embodiment of a
retractable/advanceable distal tip that may be provided on an
apparatus, such as that shown in FIGS. 1-2B.
FIG. 5 is a detail of a patient's body showing a schematic of an
exemplary system for accessing the lymphatic system of the patient
including an apparatus, such as that shown in FIGS. 1-2B.
FIG. 6 is a detail of a patient's body, showing the distal portion
of a catheter positioned within a thoracic duct of the patient and
with a balloon thereon inflated to substantially isolate the
thoracic duct from the patients venous system.
FIGS. 7A and 7B are details of a patient's body, showing a distal
portion of another exemplary embodiment of an apparatus with a pair
of balloons expanded within a thoracic duct of the patient on
either side of a valve within the thoracic duct.
FIG. 8 is a detail showing a distal portion of another embodiment
of a catheter including a plurality of expandable tines adjacent a
balloon for anchoring the distal portion relative to a thoracic
duct.
FIGS. 9A-9C are side and ends views of yet another embodiment of a
catheter including a mechanically expandable member that is
expandable from a collapsed configuration (FIG. 9A) to an enlarged
configuration (FIGS. 9B and 9C) for isolating a thoracic duct.
FIG. 10 is a side view of still another embodiment of a catheter
including an expandable umbrella/hood shown in an expanded
configuration upon deployment from a delivery sheath.
FIG. 11 is a cross-section of a patient's body showing a schematic
of an exemplary system for delivering therapeutic and/or diagnostic
agents into the patient's body.
FIG. 11A is a detail of the patient's body of FIG. 11 showing a
device isolating the patient's thoracic duct from the patient's
venous system.
DETAILED DESCRIPTION OF THE EXEMPLARY EMBODIMENTS
Turning to the drawings, FIGS. 1-2B show an exemplary embodiment of
an apparatus 8 for accessing and/or isolating the lymphatic system
of a patient 90 (not shown, see, e.g., FIG. 5 for anatomical
references), e.g., to aspirate or otherwise draw lymphatic fluid
from the thoracic duct 94, as described further below. Generally,
the apparatus 8 includes a catheter or other tubular member 10
including a proximal or main portion 20, e.g., sized and/or shaped
for introduction into a blood vessel of the patient, such as a
jugular vein 92b (not shown, see FIG. 5), and a relatively smaller
distal portion 30, e.g., sized and/or shaped for introduction into
a thoracic duct 94 of the patient 90 (also not shown, see FIG. 5),
thereby defining a central longitudinal axis 18 for the apparatus
8.
A balloon or other expandable member 50 may be provided on the
distal portion 30, e.g., sized for introduction into a thoracic
duct in a collapsed configuration and expandable to an enlarged
configuration for substantially sealing and/or isolating the
thoracic duct 94, as described further below. The balloon 50 may be
formed from elastic material, e.g., such that the balloon 50 may be
inflated to multiple diameters to accommodate engaging the wall of
thoracic ducts of various sizes and/or shapes, to provide a
substantially fluid-tight seal without applying excessive forces
against the wall.
Generally, the proximal and distal portions 20, 30 of the catheter
10 have different dimensions and/or properties. For example, the
proximal portion 20 may have a substantially straight shape in a
relaxed state, yet may be sufficiently flexible to be introduced
into a patient's body 90, e.g., sufficiently flexible to be
introduced into the venous system from a percutaneous access site,
such as via a left or right internal or external jugular vein,
subclavian vein, axillary vein, or other percutaneous access site.
In an exemplary embodiment, access may be gained from the left
internal jugular vein 92b to approach the junction of the left
internal jugular vein 92b and left subclavian vein 92c, as shown in
FIG. 5. The distal portion 30 may have a curvilinear shape in a
relaxed state, e.g., a simple curved shape or a more complicated
shape including one or more curved and/or straight sections, which
may facilitate introduction of the distal portion 30 into the
thoracic duct 94, e.g., from the jugular vein 92b, as described
further below.
In addition or alternatively, the proximal portion 20 may be
substantially longer than the distal portion 30, e.g., to allow the
proximal portion 20 to be introduced into the patient's body from
an access site, e.g., into the left internal jugular vein 92b, and
manipulated to introduce the distal portion 30 into the thoracic
duct 94. For example, as shown in FIG. 1, the proximal portion 20
may include a proximal end 22 including a handle or hub 23, and a
distal end 24 coupled or otherwise including a transition 25 to the
distal portion 30. In exemplary embodiments, the proximal portion
20 may have a length from the handle 23 to the transition 25
between about three and one hundred twenty centimeters (3.0-120
cm), or alternatively between about three and thirty centimeters
(3.0-30.0 cm), and may have an outer diameter or other maximum
cross-section between about one and seven millimeters (1.0-7.0 mm),
or alternatively between about one and three millimeters (1.0-3.0
mm). The handle 23 may be larger than the proximal portion 20,
e.g., having a shape and/or otherwise configured for holding and/or
manipulating the catheter 10 from a location outside of a patient's
body.
The transition 25 may include a tapered shape, as shown, an abrupt
step-down shape (not shown), and the like to transition between the
proximal and distal portions 20, 30. If the proximal and distal
portions 20, 30 are formed from different materials, the transition
25 may connect the different materials together, e.g., by bonding
with adhesive, fusing, sonic welding, heat forming, and the
like.
The distal portion 30 may have a proximal end 32 extending distally
from the transition 25, e.g., aligned substantially axially with
the proximal portion 20, and a distal end 34 terminating in a
distal tip 35. In exemplary embodiments, the distal portion 30 may
have a length from the proximal end 32 to the distal tip 35 between
about one and ten centimeters (1.0-10.0 cm), and may have an outer
diameter or other maximum cross-section between about half to five
millimeters (0.5-5.0 mm), or alternatively between about half and
two millimeters (0.5-2.0 mm). Thus, the distal portion 30 may be
substantially shorter than the proximal portion 20, e.g., such that
the proximal portion 20 may extend from a percutaneous access site
(not shown) into the junction of the left internal jugular vein 92b
and the left subclavian vein 92c, and the distal portion 30 may
simply curve and enter the thoracic duct 94, as described further
elsewhere herein.
The distal portion 30 may have a substantially uniform outer
diameter between the proximal end 32 and the distal tip 35, or the
diameter may vary, e.g., tapering at or adjacent the distal tip 35
to provide a substantially atraumatic distal tip 35.
In addition, the distal portion 30 may have a flexibility greater
than the proximal portion 20. For example, the proximal portion 20
may have sufficient column strength, stiffness, torque, and the
like such that the proximal portion 20 may be manipulated from the
handle 23 without substantial risk of the distal end 24 of the
proximal portion 20 buckling or kinking, while providing sufficient
flexibility to accommodate introduction into curved vessels within
the patient's body. In exemplary embodiments, the proximal portion
20 may have a substantially rigid or semi-rigid proximal end 22,
e.g., to facilitate advancement of the distal portion from the
handle 23, while the distal end 24 may be semi-rigid or flexible.
Moreover, the device properties may be optimized to responsively
translate manipulation of the proximal end 22 into movement of the
distal portion 30, e.g. by means of rotation, torque, angular
manipulation, withdrawal, and/or advancement.
The distal portion 30 may be substantially flexible, e.g., biased
to the curvilinear shape when free from external forces, yet
flexible to accommodate bending, compressing (of the distal tip 35
towards the proximal portion 20), and/or other movement of the
distal portion 30 to facilitate introducing the distal tip 35 into
the thoracic duct. In exemplary embodiments, the distal portion 30
may be formed from PEBAX, urethane, silicone, and/or other soft
and/or flexible materials, e.g., having substantially uniform
properties along the length of the distal portion 30, or becoming
progressively (or otherwise) softer and/or more flexible from the
proximal end 32 to the distal tip 35. The proximal and distal
portions 20, 30 may be formed from different materials to provide
the desired flexibility. For example, the proximal portion 20 may
include a reinforcement layer, e.g., braiding and the like between
inner and outer layers (not shown), while the distal portion 30 may
simply include a single layer or vice versa. Alternatively, a
different reinforcing layer (e.g. braid, coil, stent-like structure
or other scaffolding) may be used in the proximal and distal
portions 20, 30. For example, a reinforcing structure may include a
laser-cut tubular structure (e.g., formed from Nitinol, stainless
steel, cobalt chromium, and the like) having a structure that may
accommodate a substantially straight shape and a desired
curvilinear shape without substantial permanent deformation.
Further, a reinforcing structure may be shape set (e.g., by heat
treating, annealing, plastically deforming, and the like) in order
to maintain a desired curvilinear shape in the distal portion
30.
In addition or alternatively, relative flexibility may be obtained
by providing different wall thicknesses, e.g., from the same or
different materials. For example, as shown in FIGS. 2A and 2B, the
proximal portion 20 may have a relatively larger wall thickness
than the distal portion 30, which may enhance relative flexibility
of the distal portion 30. In exemplary embodiments, the wall
thickness of the proximal portion 20 may be between about 0.1 and
three millimeters (0.1-3.0 mm), while the wall thickness of the
distal portion 30 may be between about 0.1 and two millimeters
(0.1-2.0 mm).
As shown in FIG. 1, the distal portion 30 may include multiple
substantially straight sections between curved sections, e.g., to
provide a "hook" shape having an overall angle of curvature equal
to or greater than ninety degrees, e.g., between about ninety and
three hundred sixty degrees)(90-360.degree., or between about
ninety and one hundred fifty degrees)(90-150.degree.. Such radii of
curvature may facilitate introduction into the thoracic duct 94,
which may connect near the junction of the jugular, subclavian, and
brachiocephalic veins 92 at an acute angle, such that a radius of
curvature greater than ninety degrees)(90.degree. may be necessary
to align the distal tip 35 with the thoracic duct 94 when the
proximal portion 20 is within the left internal jugular vein 92b,
as described further elsewhere herein.
In an alternative embodiment, shown in FIG. 3A, the distal portion
30a may include a single substantially continuous radius of
curvature approaching one hundred eighty degrees)(180.degree.. In a
further alternative, shown in FIG. 3B, the distal portion 30b may
have a more complicated curvilinear shape, e.g., including a first
straight section between a bend and a radiused section ending in a
substantially straight distal tip (which may carry a balloon, not
shown). In yet another alternative, shown in FIG. 3C, the distal
portion 30c may include a continuous curved shape including a first
bend in an opposite direction to the main radius of curvature of
the distal portion 30c. Such shapes may orient the distal tip 35 of
the catheter 10 back towards the proximal end 22 with the distal
tip 35 defining a desired angle relative to the longitudinal axis
18 within the proximal portion 20.
In still another alternative, the distal portion 30 may include a
curved section of constant or variable radius having an arc angle
of between about zero and three hundred sixty
degrees)(0.degree.-360.degree. and a radius of curvature between
about one and fifteen millimeters (1.0-15.0 mm). Further
alternatively, the distal portion 30 may include one or more
discrete bends, creating a distal shape having a width between
about two and thirty millimeters (2.0-30.0 mm). More generally, any
of the foregoing shapes may be optimized to locate the distal tip
35 at or near the thoracic duct ostium and simultaneously align the
tip vector with the entry vector of the thoracic duct 94.
Furthermore, the shape of the distal portion 30 may be sufficiently
resilient to return to its pre-set shape, e.g. after introduction
through a sheath, repeated manipulation, and the like.
Optionally, the distal portion 30 may include one or more features
to facilitate identification and/or localization of the distal
portion 30, e.g., the balloon 50 and/or distal tip 35, within a
patient's body using external imaging. For example, one or more
echogenic features, may be provided on or in the wall of the
balloon 50 and/or on the distal tip 35, which may facilitate
monitoring the distal portion 30 using ultrasound imaging. Such
exemplary features may include doping or coating with tungsten,
tungsten carbide, titanium dioxide, iron oxide, zinc oxide,
platinum, gold, barium, bismuth, and/or titanium; echogenic surface
modifications such as reflective gratings, surface depression
and/or projections; inclusions, for example, of glass particles,
air bubbles, and the like, including those described in U.S. Pat.
No. 5,921,933, the entire disclosure of which is expressly
incorporated by reference herein. Alternatively, radiopaque and/or
other markers (also not shown) may be provided to facilitate
monitoring the distal portion 30 using fluoroscopy or other
external imaging.
Returning to FIGS. 1-2B, the catheter 10 may include one or more
lumens 26, 27 extending therethrough, e.g., from the proximal end
22 of the proximal portion 20 to the distal portion 30. For
example, as shown in FIG. 1, an aspiration or infusion lumen 26 may
be provided that communicates with a port 23a in the handle 23 and
extends through the entire proximal and distal portions 20, 30 to
one or more inlet (or outlet) ports 36 adjacent the distal tip 35.
As best seen in FIGS. 2A and 2B, the aspiration lumen 26 may
include a relatively large region 26a within the proximal portion
20 and a relatively small region 26b within the distal portion 30.
In exemplary embodiments, the proximal region 26a of the lumen 26
may have an inner diameter (or other maximum cross-section) between
about one and five millimeters (1.0-5.0 mm), while the distal
region 26b may have an inner diameter (or other maximum
cross-section) between about 0.1 and three millimeters (0.1-3.0
mm).
The smaller diameter of the distal region 26b may allow the outer
diameter of the distal portion 30 to be minimized, e.g., to provide
desired flexibility and/or minimize the size of the distal portion
30 to facilitate introduction into the thoracic duct 94, while the
larger diameter of the proximal region 26a may allow lymph or other
fluids to be drawn through the catheter 10 more easily. For
example, the larger diameter over most of the length of the
catheter 10 may expose the fluid to lower friction, which may
increase flow rate and/or reduce the risk of lysing or otherwise
damaging cells or other components of the fluid being aspirated or
delivered through the lumen 26 of the catheter 10.
As shown in FIGS. 2A, 2B, and 4A, the aspiration lumen 26 may
communicate with a single inlet port 36 in the distal tip 35, e.g.,
aligned with the central longitudinal axis 18. Alternatively,
multiple inlet ports may be provided on the distal tip, e.g., to
reduce the risk of a single or multiple ports becoming occluded
with fluid or debris and/or contacting and sucking the wall of the
thoracic duct or other body lumen against the distal tip 35, which
may otherwise prevent fluid from being drawn into the lumen 26. For
example, as shown in FIG. 4B, the distal tip 35a may include a
plurality of side ports in addition to the axial inlet port 36a,
or, as shown in FIG. 4C, one or more slots (two shown) may be
provided that extend partially from the axial inlet port 36b.
In addition, turning to FIG. 2C, the catheter 10 may include an
inflation lumen 27, e.g., extending through the proximal and distal
portions 20, 30 and communicating with an interior of the balloon
50. The inflation lumen 27 may communicate with a port 23b on the
handle 23, shown in FIG. 1, which may allow a source of inflation
and/or vacuum, e.g., a syringe and the like (not shown), to be
coupled to the catheter 10 and communicate with the interior of the
balloon 50, e.g. to allow the balloon 50 to be inflated and
collapsed, as described elsewhere herein. Alternatively, another
expanded member, e.g., a mechanically expandable frame and the like
(not shown, see, e.g., FIGS. 9A-9C), may be provided on the distal
portion 30 instead of the balloon 30. In this alternative, a
mechanical actuator, e.g., a slider, wheel, and the like (also not
shown, may be provided on the handle 23 that is coupled to the
frame or other expandable member for directing the expandable
member between collapsed and enlarged configurations.
Optionally, the catheter 10 may include one or more additional
lumens, if desired. For example, an infusion lumen (not shown)
separate from the aspiration lumen 26 may be provided, which may
allow infusion of fluids or agents through the catheter 10 to one
or more outlets (also not shown) on the distal portion 30,
independent of aspiration or removal of fluid through the lumen 26.
Infusion of fluids may be into the thoracic duct 94 or into the
vein(s) at any point along the course of the catheter 10. Infused
fluids may include at least some part or all of fluids aspirated by
means of the same catheter. In addition, a guidewire lumen and/or a
stylet lumen (not shown) may be provided that extends through the
proximal portion 20 into the distal portion 30, e.g., for at least
partially straightening and/or supporting the distal portion 30
during introduction into a patient's body, as described elsewhere
herein.
Turning to FIGS. 5 and 6, the apparatus 8 may be used to perform a
medical procedure within the patient's body 90 that includes
accessing the thoracic duct 94, which may be related to any of the
conditions and/or treatments described elsewhere herein. Initially,
the catheter 10 may be introduced into the patient's body 90, e.g.,
into the venous system from a percutaneous access site, such as the
left or right internal or external jugular, subclavian, axillary,
anterior cubital, or femoral veins.
To facilitate introduction and/or navigation of the catheter 10,
one or more other devices may be used in conjunction with the
catheter 10, if desired. For example, in one embodiment, a
guidewire (not shown) may be introduced and advanced from the
percutaneous access site, through any intervening vessels into the
junction of the left internal jugular vein 92b and left subclavian
vein 92c, and into the thoracic duct 94. The guidewire may be
backloaded into the inlet port 36 of the distal portion 30 and
through the aspiration lumen 26 (or through a separate lumen, e.g.,
a dedicated guidewire lumen, not shown, if provided on the catheter
10). The catheter 10 may then be advanced over the guidewire into
the access site and intervening vessels, and at least the distal
tip 35 of the distal portion 30 may be introduced into the thoracic
duct 94.
In addition or alternatively, other devices may be used to at least
partially straighten and/or otherwise support the distal portion 30
of the catheter 10. For example, a stylet (not shown) may be
positioned within the catheter 10, e.g., within the aspiration
lumen 26 or a separate lumen (not shown) such that the stylet
enters at least partially into the distal portion 30, thereby
directing the distal portion 30 from its relaxed curvilinear shape
to a less curved or substantially straight configuration (not
shown) and/or otherwise supporting the distal portion 30 from
buckling or kinking. The distal portion 30 may then be introduced
through the access site and any intervening vessels until the
distal tip 35 is located adjacent the thoracic duct 94, e.g.,
within the junction of the jugular and subclavian veins 92b, 92c.
The stylet may be sufficiently flexible to accommodate introducing
the distal portion 30 through any bends or tortuous anatomy
encountered between the access site and the thoracic duct 94. Once
the distal tip 35 is located adjacent the thoracic duct 94, e.g.,
within the junction of the left internal jugular vein 92b and the
left subclavian vein 92b, the stylet may be removed, thereby
allowing the distal portion 30 to return towards its relaxed,
curvilinear configuration. Alternatively, one or more shaped
stylets may be used to accentuate, alter, essentially create the
shape of the distal portion 30. Further, a stylet may be used to
direct the distal portion 30 toward and/or into the thoracic duct
94, e.g., by independent and/or co-manipulation (e.g. twisting,
advancing, retracting) of the stylet and the catheter 10.
In another alternative, a sleeve, sheath, cover, and the like (also
not shown) may be provided over the catheter 10 until the distal
portion 30 is sufficiently covered, e.g., to at least partially
straighten and/or support the distal portion 30. The distal portion
30 may then introduced into the patient's body 90 until the distal
tip 35 is disposed adjacent the thoracic duct 94, whereupon the
cover may be removed to expose and release the distal portion 30,
again thereby allowing the distal portion 30 to return towards its
relaxed, curvilinear configuration.
With the distal portion released or exposed within the junction,
the proximal portion 20 of the catheter 10 may then be manipulated,
e.g., advanced and/or retracted, rotated, and the like until the
distal tip 35 enters the thoracic duct 94, as shown in FIG. 5. For
example, without a guidewire, the catheter 10 may be manipulated
until the distal portion 30 "hooks" the ostium of the thoracic duct
94. Because of the soft and/or flexible nature of the distal
portion 30, such manipulation may be completed without substantial
risk of perforation or other damage to the vessels. In addition,
given that the thoracic duct 94 may extend at an angle almost one
hundred eighty degrees relative to the left internal jugular vein
92b, the angle of the distal portion 30 may facilitate orienting
the distal tip 35 "backwards" towards the ostium of the thoracic
duct 94.
Once the distal tip 35 is placed within the ostium of the thoracic
duct 94, the catheter 10 may be retracted or otherwise manipulated
to direct the distal portion 30 further into the thoracic duct 94.
For example, if the catheter 10 is to be introduced into the left
internal jugular vein 92b, as shown in FIG. 5, the length of the
catheter 10 may be substantially shorter than most catheters,
thereby providing a more direct relationship of movement between
the proximal end 22 and the distal portion 30 since the catheter 10
is less likely to twist, compress, stretch, and the like between
the proximal end 22 and the distal portion 30.
If the catheter 10 is manipulated to place the distal tip 35 at the
ostium of the thoracic duct 94, the catheter 10 may simply be
retracted (e.g., upwardly) to pull the distal tip 35 up into the
thoracic duct 94, e.g., as shown in FIG. 6. In an exemplary
embodiment, the distal portion 30 may pass through the terminal
valve 95a of the thoracic duct 94 until the balloon 50 is
positioned between the terminal valve 95a and the next valve 95b
within the thoracic duct 94. The balloon 50 may then be inflated to
engage the wall of the thoracic duct 94 and substantially seal
and/or isolate the thoracic duct 94 from the veins 92.
Optionally, navigation to the thoracic duct 94 may be aided using
external imaging, such as ultrasound imaging. For example, as
described elsewhere herein, the distal portion 30 of the catheter
10 may include one or more echogenic features, which may facilitate
identification and monitoring the balloon 50 and/or the distal tip
35. Because the thoracic duct 94 is located near the surface, i.e.,
close to the patient's skin, an ultrasound imaging device placed on
or near the patient's skin may provide high resolution
visualization of the region including the thoracic duct 94 and
adjacent veins 92 to facilitate monitoring the distal portion 30
until the distal tip 35 and balloon 50 are positioned as
desired.
In addition or alternatively, tactile feedback and/or manipulation
may be used to facilitate positioning the distal portion 30. For
example, given the close proximity of the thoracic duct 94 and
neighboring veins 92 to the skin, it may be possible to feel the
catheter 10 by placing the user's fingers on the patient's
overlying skin and pressing against the skin and intervening
tissues. Such pressure may also be used to physically manipulate
the distal portion 30, e.g., in addition to manipulation of the
proximal end 22, to direct the distal tip 35 into the thoracic duct
94.
In addition or alternatively, other imaging may be used, such as
fluoroscopy, MRI, CT, and/or direct visualization, e.g., using an
imaging element carried on the distal portion 30 of the catheter
10. Exemplary imaging elements and methods for using them are
disclosed in U.S. Publication Nos. 2011/0034790, 2007/0015964,
2006/0084839, and 2004/0097788, the entire disclosures of which are
expressly incorporated by reference herein.
Optionally, additional methods may be used to facilitate
introducing the distal tip 35 and balloon 50 through the terminal
valve 95a, e.g., instead of simply pushing the distal tip 35
through the valve 95a. For example, the terminal valve 95a may be
monitored using external imaging or otherwise monitored to
coordinate timing of movement of the terminal valve 95a with
physiological events, e.g., heart rate, and the like, until the
terminal valve 95a naturally opens, whereupon the distal tip 35 may
be advanced through the open valve 95a into the thoracic duct 94.
Alternatively, the user may trigger opening of the terminal valve
95a, e.g., by increasing lymph within the patient's body, for
example, by squeezing tissue in the arm or leg.
In another alternative, a negative pressure may be created within
the junction, e.g., by aspirating into the catheter 10 or
otherwise, with the resulting vacuum causing the terminal valve 95a
to open and allow the distal tip 35 to be advanced into the
thoracic duct 94. In other alternatives, the user may simply
periodically probe the terminal valve 95a by gently advancing the
distal tip 35 against the valve 95a and/or by rotating the catheter
10 to screw the distal tip 35 through the valve 95a. Further
alternatively, the balloon 50 (or other distal expandable member)
may be at least partially expanded to assist in centering the
distal tip 35 in or near the ostium in order to more easily cross
the valve 95a.
In yet another alternative, a helical tip member (not shown) may be
provided on the distal portion 30 that extends from the distal tip
35, which may be rotated to guide the distal tip 35 through the
terminal valve 95a. In these alternatives, the distal portion 30
may pass through the terminal valve 95a until the balloon 50 is
positioned between the terminal valve 95a and the next valve 95b
within the thoracic duct 94. The balloon 50 may then be inflated to
engage the wall of the thoracic duct 94 and substantially seal
and/or isolate the thoracic duct 94 from the veins 92.
With the balloon 50 expanded to substantially isolate the thoracic
duct 94, fluid may be aspirated into the lumen 26 of the catheter
10 and collected, e.g., as described elsewhere herein, fluid may be
delivered into the thoracic duct 94, and/or other desired
procedures may be performed via the thoracic duct 94.
In an alternative embodiment, shown in FIG. 4D, the catheter 10'
may include a movable distal tip 35,' which may be directed axially
closer to or away from the balloon 50.' For example, the balloon
50' may be attached to the distal end of an outer tubular member
30,' and an inner tubular member 37' may extend through the outer
tubular member 30' and the balloon 50,' and terminate in the distal
tip 35.' Thus, movement of the inner tubular member 37' relative to
the outer tubular member 30' may move the distal tip 35' relative
to the balloon 50.' In this alternative, the balloon 50' may serve
to substantially center the distal tip 35' relative to the valve(s)
95 within the thoracic duct 94 (not shown in FIG. 4D), e.g., such
that the distal tip 35' may be advanced or retracted as desired
relative to the valve(s) 95 to facilitate access, removal of fluid,
and/or performing other procedures within the thoracic duct 94.
Optionally, the suction pressure used to aspirate lymph within the
thoracic duct 94 may be adjusted, e.g., to substantially match the
individual patient's maximum lymph flow. If the patient lymph flow
changes over time, this method anticipates adjustment of pressure
over time, both decreasing suction pressure over time, and
increasing suction pressure over time, as desired.
In another option, fluids or other substances may be infused into
the thoracic duct 94 or vein via the catheter 10, if desired, e.g.,
in a substantially continuous or oscillatory manner. For example,
one or more of the following may be infused: blood contaminated
lymph, lymph with greater concentrations of desired substances, and
the like, as described elsewhere herein.
In another embodiment (not shown), the catheter may include a
distal end and a balloon sized to be introduced into the thoracic
duct. For example, the distal end may be advanced beyond a valve in
the thoracic duct such that the balloon may be inflated beyond the
valve. In addition or alternatively, the catheter may include one
or more other features for securing and/or sealing distal to a
valve, including one or more compliant rings, radial
filaments/brushes, and/or other passive fixation devices (not
shown) that may at least partially resist retraction or avoid
spontaneous dislodgement of the catheter during use. In addition or
alternatively, active fixation, such as suction, may be used to
substantially fix the distal end of the catheter at a desired
location, e.g., within the thoracic duct.
Turning to FIGS. 7A and 7B, another embodiment of a catheter 110 is
shown that includes a pair of balloons 150 spaced apart axially
from one another on a distal portion 130 of the catheter 130. The
balloons 150 may communicate with a single inflation lumen (not
shown) such that the balloons 150 may be inflated and/or collapsed
substantially simultaneously. Alternatively, the balloons 150 may
communicate with separate inflation lumens (also not shown) such
that the balloons 150 may be inflated and/or collapsed
independently of one another. The catheter 110 may have a size,
length, and/or shape configured to be introduced and/or manipulated
using a handle or hub on a proximal end (not shown) of the catheter
110, similar to other embodiments herein.
As shown in FIGS. 7A and 7B, a distal tip 135 of the catheter 110
may be introduced into the thoracic duct 94 until the balloons 150
pass beyond the terminal valve 95a. Optionally, as shown in FIG.
7A, the balloons 150 may be spaced apart sufficiently from one
another such that the balloons may be provided on either side of
the next valve 95b within the thoracic duct 94, i.e., with a
proximal balloon 150a between a first and second valve 95a, 95b,
and a distal balloon 150b between the second and third valves 95b,
95c. Such an arrangement of balloons 150 may provide enhanced
stability for the distal portion 130 and/or improved sealing of the
thoracic duct 94.
Optionally, the balloons 150 may be configured such that the
balloons 150 may be positioned with a valve 95b located between the
balloons 150. When the balloons 150 are inflated, they may squeeze
or otherwise engage the valve 95b to enhance sealing of the
thoracic duct 94 using the valve 95b in addition to the balloons
150 engaging the wall of the thoracic duct 94. In another option,
shown in FIG. 7B, the balloons 150 may be positioned on either side
of the terminal valve 95a such that the distal balloon 150b is
positioned between the first and second valves 95a, 95b, and the
proximal balloon 150a engages the ostium of the thoracic duct 94
outside the terminal valve 95a, which may reduce the risk of blood
entering the thoracic duct 94 from the veins 92. Further
alternatively, the balloons 150 may be slidably disposed relative
to one another (not shown) such that they may be brought together
or moved apart, e.g., to capture and/or release a valve positioned
between them. Further alternatively, one or more balloons may
include different surface properties, e.g. a lubricious distal
surface (e.g., using a hydrophilic coating, lubrication, surface
features, and the like), e.g., to facilitate valve crossing and a
less lubricious proximal surface to, e.g. to decrease the chance of
inadvertent removal.
Turning to FIG. 8, still another embodiment of a catheter 210 is
shown that includes a plurality of tines 254 on the distal portion
230 adjacent the balloon 250. The tines 254 may be biased to expand
outwardly, but may be compressible inwardly, e.g., using an
external sleeve or other constraint (not shown), which may be
removed, e.g., after positioning the balloon 250 at a desired
position within a thoracic duct (also not shown). When the tines
254 are deployed, they may engage the wall of the thoracic duct to
anchor the distal portion 230 to prevent movement even if the
balloon 250 is collapsed. The tines 254 may include substantially
blunt free ends to engage the thoracic duct without penetrating or
damaging the wall, or may include sharpened tips and/or barbs (not
shown), which may be substantially permanently or indefinitely
engage the wall of the thoracic duct. Thus, this embodiment may be
used to secure the catheter 210 substantially indefinitely, e.g.,
for a long-term implant that is used to intermittently isolate the
thoracic duct by expanding the balloon 250, e.g., to collect
lymph.
When not needed, the balloon 250 may be collapsed allowing normal
function of the thoracic duct while the tines 254 prevent migration
of the catheter 210 from the thoracic duct. If desired, the
catheter 210 may be removed, e.g., by directing a sheath or other
tubular member (not shown) into the thoracic duct to recapture
and/or otherwise collapse the tines 254.
Alternatively, other features may be provided on the catheter,
e.g., in addition to or instead of the tines 254 to maintain the
distal end of the catheter 210 (or any of the embodiments herein)
in a desired position, e.g., within the thoracic duct. Exemplary
features may include providing silicone or other anti-slip
materials on the distal end, a Nitinol or other expandable
anchoring structure, an anchor ring, and the like (not shown).
Turning to FIGS. 9A-9C, another embodiment of a catheter 310 is
shown that includes an expandable frame 350 on a distal portion 330
including a set of wires or struts that may be manipulated from a
proximal end (not shown) of the catheter 310. For example, an
actuator on the proximal end (not shown) may be activated to direct
the frame from a collapsed configuration (shown in FIG. 9A) to an
enlarged configuration (shown in FIG. 9B). The size of the frame
350 may be sufficient to engage a wall of a thoracic duct when the
distal portion 330 is introduced into the thoracic duct, as
described elsewhere herein.
As shown in FIG. 9C, the frame 350 may carry a nonporous membrane
that may be directed across the thoracic duct when the frame 350 is
expanded to substantially seal the thoracic duct. Thus, the frame
350 may operate similar to the balloons described elsewhere herein,
except that the frame 350 is mechanically actuated rather using
fluid to inflate and collapse the balloons.
Turning to FIG. 10, yet another embodiment of a catheter 410 is
shown that includes an expandable frame 450 on a distal portion 430
including a set of wires or struts 452 carrying a non-porous
membrane 454. The frame 450 may be biased to an enlarged
configuration, e.g., in which the struts are shaped to engage
and/or enter the ostium of a thoracic duct, yet may be resiliently
compressed into a delivery configuration, e.g., when placed within
a delivery catheter 460. Alternatively, the frame 450 may be
actuated from a proximal end (not shown) of the catheter 410, e.g.,
similar to the previous embodiments. The size of the frame 450 may
be sufficient to engage the ostium adjacent the thoracic duct, or
may be sized for introduction into the thoracic duct such that the
membrane 454 sealingly engages the wall of the thoracic duct, e.g.,
when the distal portion 430 is introduced into the thoracic duct on
either side of one or more valves, similar to other embodiments
herein.
Turning to FIG. 5, the apparatus 8 shown in FIG. 1, or any of the
other embodiments herein, may be part of a system 6 including one
or more external components for performing a medical procedure,
e.g., which may involve removing lymphatic fluid from the patient's
body 90 via the thoracic duct 94, introducing agents or devices
(not shown) into the thoracic duct 94, and/or infusing the removed
lymphatic fluid, components thereof, and/or other agents into other
locations within the patient's body 90. For example, one or more
external devices may be provided that are coupled to the proximal
end 22 of the catheter 10, e.g., for detecting, separating,
collecting, and/or infusing lymphatic fluid and/or other fluids, as
described in U.S. Publication No. 2011/0276023, the entire
disclosure of which is expressly incorporated by reference herein.
The external components may be provided integrated into a single
device or may be provided as separate discrete components that are
coupled to one another (e.g., along a fluid path, electrically,
and/or otherwise).
In the example shown schematically in FIG. 5, the external
components may include a detector or analyzer 60, a controller 62,
a separator or filter 64, a waste container 66, a storage container
68, and an infusion device 70. One or more of the components may
include a pump or source of vacuum or pressure, e.g., for removing
fluid from the patient's body and/or delivering fluid into the
patient's body 90 via the catheter 10, or infusing fluids via the
infusion device 70, as described further below. In alternative
embodiments, one or more of the components may be omitted. For
example, the catheter 10 may simply be coupled directly to the
storage container 68, e.g., with or without a source of vacuum to
facilitate collection of lymphatic fluid (and any agents that end
up within the lymphatic system).
The detector 60 may be coupled to the proximal end 22 of the
catheter 10, e.g., to the port 23a on the handle 23, for receiving
fluids that are drawn through the lumen 26 of the catheter 10 from
the inlet port 36 in the distal tip 35 (not shown in FIG. 5, see,
e.g., FIGS. 2A, 2B). The detector 60 may include one or more
sensors (not shown), e.g., for distinguishing between lymphatic
fluid and blood. In addition or alternatively, one or more sensors
may be provided on the distal end 34 of the catheter 10, e.g., to
detect when the thoracic duct is accessed and/or sealed from the
venous system. In exemplary embodiments, the sensor(s) may include
one or more optical sensors (e.g., for detecting the presence of
red blood cells by light transmission or reflection
characteristics), chemical sensors (e.g., for detecting one or more
of pH, oxygen concentration, lactate, leukocyte esterase, and the
like), sensors for measuring hematocrit, electrical sensors (e.g.,
for measuring impedance), temperature sensors, mechanical sensors
(e.g., for detecting pressure waves, which may differ between the
venous system and the thoracic duct; for flow detection, e.g., by
Doppler ultrasound), filter devices sized to constituents of whole
blood, and the like. In addition or alternatively, a sensor may be
provided that is adapted to detect the presence of an exogenous
marker introduced into the lymphatic system, such as a dye (e.g.,
methylene blue), an ingested marker, a fluorescent marker, and the
like.
For example, a pump or other source of vacuum or pressure (not
shown) within or coupled to the detector 60 may be selectively
activated, e.g., by the controller 62 (or alternatively manually by
a user, if desired), to remove fluid from the patient's body via
the catheter 10 through the detector 60 to the separator 64. The
controller 62 may automatically analyze sensor data from the
sensors to identify whether the fluid is lymphatic fluid, blood, or
other fluid.
For example, if the controller 62 determines that the fluid
includes blood, the controller 62 may direct the fluid to the waste
container 66, e.g., through the separator 64 or directly. In
addition or alternatively, if the controller 62 detects the
presence of a significant amount blood in the fluid (based on data
from the detector 60 or otherwise) or detects a loss of seal (e.g.,
due a sudden pressure change in the fluid being removed via the
catheter 10), the controller 62 may shut down the pump, close a
shut-off valve (not shown) in the detector 60, or otherwise stop
flow of fluid from the catheter 10 into the detector 60 and/or the
rest of the system 6. This safety mechanism may be active, i.e.,
shut down automatically, or passive, i.e., merely warn the
user.
In an exemplary embodiment, the separator 64 may include a valve
(not shown) including an inlet 64a that communicates with the
detector 60, a first outlet 64b communicating with the storage
container 68, and a second outlet 64c communicating with the waste
container 66. The valve may be selectively operable between the
first and second outlets 64b, 64c by the controller 62, e.g., to
direct undesired fluid, e.g., blood, to the waste container 66, and
desired fluid, e.g., lymphatic fluid or components thereof, to the
storage container 68. Alternatively, or in addition, the separator
64 may include one or more devices for separating and/or filtering
various components of lymphatic fluid, including various types of
cells, proteins, electrolytes, water, and/or other constituent
parts of lymphatic fluid, and/or target agents that have transited
into the lymphatic system. For example, chemotherapy or other
agents may be substantially separated from other components in
order to selectively remove the agents from a patient's body, e.g.,
to avoid systemic delivery of the agents, as described elsewhere
herein.
If the controller 62 confirms that the fluid is lymphatic fluid,
the controller 62 may activate the separator 64 to direct the
lymphatic fluid or components of the lymphatic fluid into the
storage container 68. For example, if the entire lymphatic fluid is
to be collected, the separator 64 may simply divert the fluid into
the storage container 68. Alternatively, it may be desirable to
separate certain constituents of the removed fluid, e.g., lymphatic
fluid, particular cells, proteins, and the like, and/or agents
previously introduced into the patient's body. For example, the
separator 64 may include one or more of a mechanical filtration
system, an osmotic gradient system, a concentration gradient
system, a centrifuge, and the like to separate the desired
components from the rest of the fluid. Once separated, the desired
components may be delivered to the storage container 68, while the
rest of the fluid is delivered to the waste container 66.
Optionally, the controller 62 or other components of the system 6
may monitor the flow to keep track of the amount of fluid extracted
and/or to stop after a predetermined amount of fluid is extracted.
In addition or alternatively, the controller 62 may operate the
pump, vacuum source, valve, and/or other components of the system 6
periodically or otherwise intermittently, e.g., to allow
reaccumulation of fluid within the lymphatic vessels.
For example, as shown in FIG. 5, an infusion catheter 70 may be
provided that includes a proximal end 70a coupled to the storage
container 68, and a distal end 70b sized for delivering the stored
fluid into the patient's body 90. Alternatively, the lymphatic
fluid removed from the patient's body may be reinfused, e.g., after
separation, treatment, and the like, back into the thoracic duct 94
using the catheter 10 already positioned in the thoracic duct 94.
In addition or alternatively, the catheter 10 may be used to infuse
other fluid directly into the thoracic duct 94, e.g., as described
further elsewhere herein.
For example, the catheter 10 may include a single infusion lumen,
e.g., for removing lymphatic fluid and returning any desired fluids
back into the patient's body. Alternatively, the catheter 10 may
include multiple lumens (not shown), e.g., an aspiration lumen for
removing lymphatic fluid and an infusion lumen for delivering
fluids (e.g., to the thoracic duct and/or adjacent vein), such as
treated lymphatic fluid and/or other diagnostic or therapeutic
compounds. Such lumens may terminate at the distal portion of the
catheter 30 and/or more proximally. For example, the aspiration
lumen may include an inlet distally beyond the balloon, e.g., for
aspirating fluid from the isolated thoracic duct, while the
infusion lumen may include an outlet proximal to the balloon, e.g.,
to provide a fluid channel into the venous system adjacent to the
thoracic duct. In addition or alternatively, the catheter 10 may
include a working lumen sized for receiving auxiliary devices
therethrough (not shown), e.g., larger than the infusion lumen(s)
for receiving one or more guidewires, auxiliary catheters, and the
like (not shown). If the catheter 10 includes one or more balloons,
e.g., balloon 50 shown in FIG. 1, the catheter 10 may also include
one or more inflation lumens (not shown), e.g., adjacent the
aspiration, infusion, and/or working lumen(s), for inflating and/or
collapsing the balloon(s) together or independently of one another,
as described elsewhere herein.
The catheters, systems, and methods described herein may be used to
perform a variety of procedures within the patient's body, e.g.,
involving accessing the thoracic duct, removing lymphatic fluid
from the thoracic duct, and/or infusing or reinfusing fluids into
the thoracic duct. For example, agents delivered to other locations
within a patient's body may transit into the thoracic duct, and the
fluid may be removed to prevent such agents from entering the
patient's venous system, which may otherwise risk systemic exposure
of the agents to the patient.
Turning to FIGS. 11 and 11A, an exemplary embodiment of a system
510 is shown that includes a syringe 520 including a chemotherapy
drug and/or other therapeutic and/or diagnostic agent 530, and an
apparatus 8 for sealing the thoracic duct and/or removing fluid
from the thoracic duct (which may be any of the embodiments
described elsewhere herein or in the applications incorporated by
reference), e.g., to prevent systemic exposure of the agent(s) 530
delivered using the syringe 520. The system 510 may be used to
temporarily access and/or isolate the thoracic duct 94.
Alternatively, the apparatus 8 may be implanted entirely within the
patient's body 90 (not shown), e.g., to allow chronic access to the
thoracic duct 94, allow selective isolation and/or removal of
lymphatic fluid.
Generally, the syringe 520 includes a barrel 522 defining an
interior 524 containing the agent(s) 530, a needle 526 coupled to
the barrel 522, and a plunger 528 slidable within the barrel 522
for delivering the agent(s) 530 within the barrel 522 through the
needle 526 into a patient's body 90, as described further below.
Alternatively, other delivery devices (not shown) may be used for
localized delivery of the agent(s) within a target treatment site
within the patient's body 90. For example, a catheter (not shown)
may be provided that includes a distal end sized for introduction
into the patient's body 90, e.g., into the patient's vasculature or
other body lumens, which may include a lumen for delivering the
agent(s) within a target body lumen e.g., within micro-bubbles,
micro-particles, and the like (not shown), and/or may include a
needle (also not shown) deployable from the catheter for delivering
the agent(s) into tissue adjacent a body lumen within which the
catheter distal end is positioned. In the exemplary embodiment
shown in FIG. 5, the agent(s) 530 may be injected directly into or
adjacent a tumor 96, e.g., within a patient's breast, ovary, lung,
gastrointestinal (GI) tract, and the like. In other alternatives,
the agent(s) may be injected into an artery supplying blood to a
tumor and/or the agent(s) may be taken orally.
The agent(s) 530 may include particles sized and/or otherwise
formulated for preferential uptake into the lymphatic system. For
example, with reference to FIG. 5, at the level of the capillary
bed, lymphatic channels 94a consist of overlapping fenestrations,
permitting uptake of macrolecules and compounds too large to return
through venous capillaries. If the particles of the agent(s) 530
have an outer diameter or other cross-section larger than about
thirty to forty nanometers (30-40 nm) and smaller than about one
hundred nanometers (100 nm), the particles may pass freely from the
interstitium into lymphatic capillary channels 94a and transit into
the thoracic duct 94. In contrast, compounds larger than about one
hundred nanometers (100 nm) remain confined to the site of
injection while compounds smaller than about forty nanometers (40
nm) may pass into venous capillaries.
For example, liposomal formulations of existing chemotherapy agents
may be used in which the agents are encapsulated within lipid
membranes, e.g., within a micelle, to provide particles having
appropriate sizes. Alternatively, large lipophilic moieties or
functional groups may be attached, at least temporarily, to the
agent(s). In an exemplary embodiment, a chemotherapy agent may be
encapsulated in a lipid membrane having an outer diameter between
about twenty and one hundred nanometers (20-100 nm) or between
about forty and fifty nanometers (40-50 nm) such that the agent may
preferentially pass into the lymphatic capillary channels 94
(rather than the venous capillaries, not shown) and transit into
the thoracic duct 94. In addition or alternatively, the agents may
be modified or augmented using one or more additional methods, such
as pegylation, positive or negative charging, or dye or fluorescent
reporter conjugation.
The systems and methods herein may be particularly useful when
treating cancers or metastases in locations significantly drained
by the lymphatic system and/or in close proximity to the thoracic
duct, e.g., the breast, lung, GI tract, and the like. In addition
or alternatively, the systems and methods herein may be used to
treat cancers that preferentially reside within the lymphatic
system, including lymph nodes, such as lymphoma, and other blood
borne malignancies, lymphatic and lymph node metastases derived
from other primary tumors, and the like.
In an exemplary method, shown in FIG. 11, the syringe 520 may be
used to inject the agent(s) 530 directly into or adjacent a tumor
96, e.g., via percutaneous access, i.e., by sticking the needle 522
through the patient's skin and intervening tissue into the tumor
96. Once the needle 522 is positioned within (or adjacent) the
tumor 96, the plunger 528 may be depressed to inject the agent(s)
530 into the target site, and then the needle 522 may be removed,
as shown. Alternatively, the agent(s) 530 may be introduced
intravenously, intra-arterially, or into other body cavities. In a
further alternative, the agent(s) 530 may be introduced directly
into the lymphatic system in either antegrade or retrograde
fashion.
Before or after delivering the agent(s) 530, an apparatus 8 may be
used to temporarily isolate the thoracic duct 94 from the patient's
venous system, e.g., at the junction of the left internal jugular
vein 92b and left subclavian vein 92c, as best seen in FIG. 11A.
For example, the apparatus 8 may be introduced into the patient's
venous system from a percutaneous entry site (not shown) and
advanced into the junction of the left internal jugular vein 92b
and left subclavian vein 92c. As shown in FIG. 11A, a balloon 50 of
the apparatus 8 may be positioned within the ostium of the thoracic
duct 94 (e.g., beyond one or more valves of the thoracic duct 94,
not shown) and then expanded to substantially seal the thoracic
duct 94. Alternatively, other devices and methods may be used to
isolate and/or access the thoracic duct 94, e.g., similar to the
embodiments described elsewhere herein and in the applications
incorporated by reference.
In an exemplary embodiment, the apparatus 8 may be introduced into
the patient's body 90 immediately after injecting the agent(s) 530
and used to isolate the thoracic duct 94 for a predetermined time,
e.g., until the agent(s) 530 are fully metabolized or otherwise
cleared by the patient's body. As the agent(s) 530 preferentially
pass from the tumor 96 into the lymphatic capillary channels and
transit into the thoracic duct 94, the apparatus 8 may prevent the
agent(s) from entering the patient's venous system.
Optionally, flow into and/or through the thoracic duct 94 may be
monitored and/or regulated using the system 510, e.g., using a
system similar to the system 6 shown in FIG. 5 and described
elsewhere herein. For example, subsequent to delivery of the
agent(s) 530, output from the thoracic duct 94 may be monitored
using the system 510, e.g., to detect when the particles of the
agent(s) 530 have entered the thoracic duct 94 using the apparatus
8 positioned within the thoracic duct 94. Before the agent(s) 530
are detected, the system 510 may regulate flow through the thoracic
duct 94, e.g., automatically or manually deflating the balloon 50
to allow lymphatic fluid (without any agent(s) 530) to return to
the patient's venous system.
Alternatively, the system 510 may be used to divert all of the
lymphatic fluid from the thoracic duct 94, e.g., via a lumen of the
apparatus 8 to one or more external components, which may monitor
and/or regulate flow of lymphatic fluid back into the patient's
body 90, e.g., via a lumen of the apparatus 8 or via intravenously
using a needle, similar to the infusion device 70 shown in FIG. 5.
For example, if the system 510 determines the lymphatic fluid is
agent-free, all of the fluid may be returned to the patient's body
90, e.g., using the apparatus 8 or intravenously. Once the presence
of an agent is detected, the system 510 may discard all of the
fluid, may filter the fluid to remove the agent(s), may deactivate
the agent(s), and return the remaining fluid to the patient's body
90, e.g., similar to the system 6.
Optionally, the system 510 may include a source of vacuum, pump, or
other device (not shown) to facilitate removing lymphatic fluid
from the thoracic duct 94, e.g., using the apparatus 8. For
example, after a predetermined time of exposure, flow through the
thoracic duct 94 may be increased to accelerate removal of the
agent(s) from the target site into the lymphatic system.
With continued reference to FIG. 11, in this manner the system 510
may enable controlling exposure time and/or transit of toxic
chemotherapeutic agents 5330 delivered into a tumor 96, e.g.,
within a breast or other tissue structure (not shown). For example,
the effects of agent(s) 530 may be concentrated in the local tissue
e.g., at the site of the tumor 96 where the agent(s) may be
delivered, by slowing transit of the agent(s) 530 into the
lymphatic system. As an example, an agent, designed for
preferential uptake to the lymphatic system, may be introduced
locally in or around the site of a breast tumor and the rate of
local depletion may be modulated by controlling the flow rate
through the thoracic duct 94, e.g. by selective occlusion or flow
restriction using the apparatus 8 and system 510. Optionally,
concentration of the agent(s) 530 present in the removed fluid may
be monitored to control exposure time and/or otherwise assessing
and controlling therapy. Thus, the system 510 may be used to
control the time that the agent(s) remain at the target site may be
controlled indirectly by controlling flow into the thoracic duct 94
and/or through the lymphatic system.
Once the agent(s) 530 enter the thoracic duct 94, the system 510
may be used to prevent the agent(s) from entering the venous
system, thereby minimizing exposure to the remainder of the
patient's body 90 and thus limiting toxicity. Such systems and
methods may be particularly useful for treating cancers or
metastases in locations significantly drained by the lymphatic
system and/or in close proximity to the thoracic duct 94, e.g.,
cancers of the breast, lung, GI tract, and the like.
In another embodiment, the system 510 may be used to treat cancers
that reside within the lymphatic system itself, including within
the lymph nodes, such as lymphoma, and/or to treat other blood
borne malignancies, lymphatic and lymph node metastases derived
from other primary tumors, and the like. For example, the apparatus
8 may be used to isolate the thoracic duct 94 and deliver one or
more agent(s) into the thoracic duct 94 in a retrograde manner to
treat cancers within the lymphatic system.
In another embodiment, the system 510 may be used to modulate the
lymphatic system before delivering one or more agents into the
patient's body. For example, before injecting agent(s) 530 into a
tumor 96, the apparatus 8 may be introduced into the patient's body
90 and used to isolate the thoracic duct 94 and remove lymphatic
fluid, e.g. to decrease volume and/or pressure within the lymphatic
system and at least transiently increase uptake of agent from
tissue into the lymphatic system. Alternatively, or in addition,
lymphatic fluid, e.g., without contamination by the agent(s), may
be removed before agent delivery and reinfused after completion of
treatment.
Further alternatively, the lymphatic system in proximity to an
organ targeted for agent delivery may be substantially isolated in
order to protect other organs. For example, distal end of the
apparatus 8 (or other catheter or device) may be sized (e.g.,
having a desired length and sufficiently small diameter) to pass
deep into the thoracic duct 94. The distal end of the apparatus may
be passed retrograde into the ostium of the thoracic duct 94 toward
the target organ (e.g., a breast, lungs, and the like), and the
balloon 50 may be expanded within the thoracic duct 94 at a
location adjacent the target organ to further isolate collected
agent.
While the invention is susceptible to various modifications, and
alternative forms, specific examples thereof have been shown in the
drawings and are herein described in detail. It should be
understood, however, that the invention is not to be limited to the
particular forms or methods disclosed, but to the contrary, the
invention is to cover all modifications, equivalents and
alternatives falling within the scope of the appended claims.
* * * * *